Classes of compounds of formula (A), particularly the 2-substituted 4-substituted 1,3-oxathiolanes pyrimidine nucleosides have been found to have potent antiviral activity. In particular, these compounds have been found to act as potent inhibitors of HIV-1 replication in T-lymphocytes over a prolonged period of time with less cytotoxic side effects than compounds known in the art (see Belleau et al (1993) Bioorg. Med. Chem. Lett. Vol. 3, No. 8, pp. 1723-1728). These compounds have also been found active against 3TC-resistant HIV strains (see Taylor et al (2000) Antiviral Chem. Chemother. Vol 11, No. 4, pp. 291-301; Stoddart et al (2000) Antimicrob. Agents Chemother. Vol. 44, No. 3, pp. 783-786). These compounds are also useful in prophylaxis and treatment of hepatitis B virus infections.
Methods for the preparation of these compounds have been disclosed in PCT publications WO 92/08717, WO 95/29176 and WO 02/102796 as well as in publications by Belleau et al (1993) Bioorg. Med. Chem. Lett. Vol. 3, No. 8, pp. 1723-1728; Wang et al (1994) Tetrahedron Lett. Vol. 35, No. 27, pp. 4739-4742; Mansour et al, (1995) J. of Med. Chem. Vol. 38, No. 1, pp. 1-4 and Caputo et al in Eur. J. Org. Chem. Vol. 6, pp. 1455-1458 (1999).
The product of the existing processes is in many cases a racemate. This racemate normally requires further processing to obtain the pure enantiomers. A preferred method for the production of single enantiomers is resolution of the racemate such as by direct preferential crystallization, crystallization of the diastereomeric salts, kinetic resolution, enzymatic resolution, selective absorption and asymmetric synthesis.
If the racemate is a true racemic compound, a homogeneous solid phase of the two enantiomers co-exists in the same cell unit. These materials may be separated via diastereomer crystallization, which generally involves reacting the racemate with an optically pure acid or base (the resolving agent) to form a mixture of diastereomeric salts that are then separated by crystallization. Other racemates may exist in the form of conglomerates, which is a compound that crystallizes with a single enantiomer in the crystal lattice. However, conglomerates are observed in less than 20% of all racemates. A conglomerate can be defined as an equimolar mixture of two crystalline enantiomers that are, in principle, mechanically separable. The phase diagram of a conglomerate displays one sharply defined minimum temperature at a mixture of 50% and 50% that is the eutectic point of the enantiomeric mixture. The success of a preferential crystallization depends on this fact.
Methods for resolving certain racemates by formation of conglomerate salts, also known as preferential crystallization or resolution by entrainment, are described in, for example, Tung et al. (U.S. Pat. No. 4,994,604), Manimaran et al. (U.S. Pat. No. 5,302,751), and Coquerel et al. (U.S. Pat. No. 6,022,409), the entire disclosures of which are hereby incorporated by reference.
A conglomerate compound crystallizes as a single enantiomer in the crystal lattice. Therefore, to be a conglomerate the IR spectrum of the racemic conglomerate salt, a 1:1 mixture of (−) and (+) crystals, must be identical to that of the single enantiomer. Another characteristic of conglomerate behavior is that the racemic conglomerate salt normally has a melting point lower that that of either single enantiomer.
If a conglomerate is obtained, it may be used for enantiomeric excess enhancement because the most soluble composition is racemic. Generally the conglomerate of X % enantiomeric excess will provide an X % yield of single enantiomer leaving behind racemic liquors.
A conglomerate may also be used in an entrainment process in which a racemic solution is seeded with a single enantiomer leading to preferential kinetic precipitation of that enantiomer.